Amide C–N bonds activation by A new variant of bifunctional N-heterocyclic carbene

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C–N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

transition state [37][38][39][40][41][42] .Connon's group designed an amide-tethered triazolium NHC for an asymmetric benzoin condensation reaction 43 .Ye's group introduced a new series of NHC derivatives bearing a free hydroxyl group and successfully achieved various enantioselective transformations 35,44,45 .Recently, our group showed that by incorporating a tethered urea or thiourea moiety, the NHC catalysts could enable a new range of asymmetric reactions 46,47 .To enhance the H-bonding donor ability, we hypothesized that squaramide could be attached to the NHC framework to activate the amide for C-N bond cleavage (Fig. 1c) 37,40,42 .Based on this hypothesis, we designed and synthesized an aminoindanol-derived triazolium NHC catalyst fused with a squaramide unit and applied it in dynamic kinetic resolution (DKR) of cyclic biaryl lactams 16,48 .The preliminary mechanistic studies by theoretical calculations and control experiments confirmed the essential role of H-bonding interaction between the amide substrate and the HBD moiety, and also verified the direct cleavage of the amide C-N bond by nucleophilic substitution of the free NHC species.This reaction exhibits mild conditions and broad substrate scope, affording atropisomeric biaryls.It also achieves the N-to-O/N-to-S acyl transfers as less conventional conversion modes (Fig. 1d).

Results and discussion
We initiated our investigation with cyclic biaryl lactam 1a and benzyl alcohol 2a in the presence of the NHC precursor 3 (Table .1).The reaction using C 2 -symmetric imidazolium pre-catalyst 3a gave a low enantioselectivity of 2% ee, although an 85% yield was obtained.The aminoindanol-derived triazolium NHC pre-catalyst 3b afforded the desired product in only 56% yield and 2% ee.In contrast, the Wasertype bifunctional NHC pre-catalyst 3c achieved moderate enantioselectivity with good conversion (70%, −36% ee) 34,49 .The enantiocontrol was significantly improved when a squaramide unit was first fused with NHC on the same skeleton (cat.3d, 99%, −66% ee).This suggested that the chimeric NHCs might be effective for the C-N cleavage of lactam and that the enhanced H-bonding strength might improve both the reactivity and enantiocontrol.We then evaluated a series of aminoindanol-derived NHC-thiourea chimeras and found that the 3,5-(CF 3 ) 2 -phenyl substituted pre-catalyst 3e gave an excellent result (99%, 94% ee).We also tried to further increase the H-bonding donor ability by replacing the thiourea with a selenourea analogue 3j, which could roughly maintain the reaction performance (99%, 92% ee).When the squaramide group was used as an HBD moiety (3k), the enantiomeric excess slightly increased to 95%, and it was chosen as the optimal catalyst.A solvent, base and temperature screening indicated that the standard conditions in entry 7 gave the best outcome.

Substrate scope
We then explored the substrate scope of alcohols under the optimized reaction conditions.As shown in Fig. 2, various substituted benzyl and heteroaryl alcohol derivatives efficiently afforded the corresponding products with high yields and excellent enantioselectivities (4a-4f).Primary alcohols, including the simplest methanol and ethanol, were suitable catalyst turnover agents (4g-4k).However, secondary and tertiary alcohols failed to complete the catalytic cycle mainly owing to steric hindrance.Some functional groups, such as cyclopropane, primary halides, and ester, were welltolerated under the reaction conditions (4k-4n).Unsaturated bonds attached to alcohols did not affect the reaction performance (4q-4s).When a diol was used, exclusive chemoselectivity of the primary hydroxyl end was observed, which could be rationalized by the kinetic factor (4t).The allyl alcohol with a long flexible chain, phytol, was also a compatible substrate for the target atropisomeric biaryl with excellent yield and ee value (4v).The crystal structure of compound 4h was determined by X-ray diffraction, confirming the axially chiral biaryl with R-configuration.
We then examined the scope of cyclic biaryl lactams (Fig. 3).Cyclic biphenyl lactams bearing different substituents (Me, OMe or OBn) on either aromatic ring gave the target products nearly quantitative yields and ee values ranging from 86% to 99% (5a-5i).The rotational barrier did not require substituents on both 2'and 6-positions, as a 2',5-disubstituted analogue could still afford the desired product and maintain conformational stability (5 g, 98%, 96% ee).Two more complex moieties were also attached to the lactam skeletons, showing a slight decrease in the reaction performance, which further demonstrated the functional group tolerance (5j and 5k).This atroposelective ring-opening protocol could also handle the phenyl-naphthyl-or phenyl-benzofuranyl-type lactams, leading to similar outcomes for both reaction efficiency and enantiocontrol (5l-5o).
Mercaptans could also act as catalyst turnover agents to afford various thioester products (Fig. 4).Benzyl thiols bearing electron-donating groups on the aromatic ring were well tolerated to give both high yield and enantioselectivities; in contrast, the electronwithdrawing group tethered analogue declined on both counts mainly owing to the occurrence of side reaction (6a-6d).Both primary and secondary thiols were compatible with the presented protocol, affording the corresponding axially chiral biaryl compounds with satisfactory results (6e-6h).When cholesterol was used, slightly lower enantioselectivity was obtained due to the chirality mismatch of the secondary thiol (6i, 95%, 86% de).The structural variations of the biaryl scaffold were also examined, most of which efficiently gave the desired products in good yields with enantiomeric excesses ranging from 88% to 99% (6j-6s).Attempts to construct atropisomers with complex skeletons showed that the reaction efficiency and enantioselectivity were slightly reduced; however, it still demonstrated the potential as a late-stage modification method (6t-6w).

Synthetic applications and mechanistic studies
We then scaled up the model reaction tenfold to demonstrate the synthetic utility of the protocol, which still performed well (product 6r, 74%, 92% ee).The resulting thioester synthon could be reduced by Et 3 SiH/Pd or NaBH 4 , affording axially chiral aldehyde 7a or alcohol 7b with preserved chirality.It also enabled rapid access to the oxadiazole motif 7c via a one-pot protocol (Fig. 5a).We then designed some experiments for mechanistic elucidation based on the concept of an acyl-azolium intermediate.The high-resolution mass spectroscopy (HRMS) analysis showed that the exact mass for the direct adduct of lactam 1a and bifunctional NHC catalyst 3k could be detected (Fig. 5b, left).This suggested that the free carbene could initiate the amide C-N bond cleavage via nucleophilic attack, forming the chirality-determining acyl-azolium intermediate.Meanwhile, the mass spectrum signal for the protonation of nitrogen anion was observed, indicating the covalent linkage mode between the lactam substrate and NHC catalyst (Fig. 5b, right).Our previous reports have shown that a proton shuttle might operate when the protonation step is a critical catalytic step.Based on this hypothesis, we tried introducing H 2 O or PhCO 2 H as an additive and found that both could improve the enantioselectivity (Fig. 5c).Even 10.0 equivalents of H 2 O could be tolerated to give a similar result.In contrast, the acidic additive did not show such high compatibility.Moreover, the conformational effect of the amide on the C-N bond cleavage reaction was investigated.The control experiment showed that the torsional strain induced by the 2',6-disubstituted pattern was an essential activation factor.Under standard conditions, the reaction was completely suppressed for unsubstituted cyclic biaryl lactams.The C-N bond also remained intact during the reaction period for acyclic amide (Fig. 5d).
The hybrid skeleton composed of triazolium NHC and squaramide as HBD was examined.As shown in Table .2, the simultaneous use of conventional triazolium NHC 3b with squaramide as a separate HBD additive could significantly increase the conversion from 56% to 98%, compared with the case without HBD additive (entries 2 and 3).Adding bifunctional NHC catalyst 3k or squaramide alone did not trigger the reaction (entries 4-6).A catalytic amount of LiHMDS could only afford a similar ring-opening product 4a, failing to achieve the catalytic version of the whole reaction cycle (entry 7).The result confirmed the unique activation ability of the newly designed NHC-HBD chimera, offering completely different catalytic properties from either NHC or HBD individual components.
The energy barriers for transition states guided by these intermediates have a more pronounced difference, further verifying Int-1A as the reaction intermediate with an energy advantage (TS-1A, 19.3 kcal mol −1 ; TS-1B, 24.2 kcal mol −1 ; TS-1C, 37.3 kcal mol −1 ).It resulted in spatial    alignment for the nucleophilic carbene centre to attack the amide, followed by a protonation step to afford the axially chiral acyl-azolium intermediate Int-2.Finally, acyl transfer by nucleophilic reagents regenerated the NHC catalyst and gave the ring-opening product 4.In this stage, other possible non-covalent interactions between catalyst and substrate skeletons are not involved or discussed 50 .
In summary, we have developed a bifunctional chimera combining triazolium NHC with squaramide as HBD, which was shown to be effective in the atroposelective ring-opening of biaryl lactams.This organocatalytic protocol formally achieved a unique amide C-N bond cleavage mode via nucleophilic attack of free carbene species.Various axially chiral biaryl amines could be readily accessed by the proposed methodology with up to 99% ee and 99% yield.By using mercaptan as a catalyst turnover agent, the resulting thioester synthon could be generated and quickly transformed into several interesting atropisomers.Both control experiments and theoretical calculations revealed the crucial role of the hybrid NHC-HBD skeleton.The squaramide moiety initially activated the amide via H-bonding, bringing it spatially close to the carbene centre.The targeted C-N bond broke via a direct NHC nucleophilic attack on the amide carbonyl.The present discovery illustrates the potential of the NHC-HBD chimera, and further application scenarios are under investigation in our laboratory.

Data availability
The X-ray structure data generated in this methodology have been deposited in the Cambridge Crystallographic Data Centre (CCDC: 2252560 for 4h, 2263709 for 7b).Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.Experimental procedures, characterizations of new compounds and DFT calculation results are included in the Supplementary Methods.For NMR and HPLC spectra of structurally novel compounds, see Supplementary Figures.All other data are available from the authors upon request.

Fig. 1 |
Fig. 1 | Catalytic amide C-N bond cleavage via bifunctional NHCs. a NHC activation for the non-aldehyde substrate.b Atroposelective ring-opening activation of amide.c Integration with non-covalent activation module.d NHC-mediated C-N activation (this work).

Fig. 3 |
Fig. 3 | The scope of cyclic biaryl lactams.See Supplementary Methods for experimental details.

Fig. 4 |
Fig. 4 | The scope of thiols and cyclic biaryl lactams.See Supplementary Methods for experimental details.

Fig. 5 |
Fig. 5 | Synthetic application and mechanism study.a Synthetic applications of axially chiral biaryl thioester.b HRMS analysis of intermediate species.c proton shuttle experiments.d Control experiments.

Fig. 6 |
Fig. 6 | Proposed catalytic cycle for the ring-opening reaction.See Supplementary Methods for experimental details.

Table . 1
| Optimization of the reaction conditions

Table . 2
| The control experiments